How Molecular Topology Can Help in Amyotrophic Lateral Sclerosis (ALS) Drug Development: A Revolutionary Paradigm for a Merciless Disease

Even if amyotrophic lateral sclerosis is still considered an orphan disease to date, its prevalence among the population is growing fast. Despite the efforts made by researchers and pharmaceutical companies, the cryptic information related to the biological and physiological onset mechanisms, as well as the complexity in identifying specific pharmacological targets, make it almost impossible to find effective treatments. Furthermore, because of complex ethical and economic aspects, it is usually hard to find all the necessary resources when searching for drugs for new orphan diseases. In this context, computational methods, based either on receptors or ligands, share the capability to improve the success rate when searching and selecting potential candidates for further experimentation and, consequently, reduce the number of resources and time taken when delivering a new drug to the market. In the present work, a computational strategy based on Molecular Topology, a mathematical paradigm capable of relating the chemical structure of a molecule to a specific biological or pharmacological property by means of numbers, is presented. The result was the creation of a reliable and accessible tool to help during the early in silico stages in the identification and repositioning of potential hits for ALS treatment, which can also apply to other orphan diseases. Considering that further computational and experimental results will be required for the final identification of viable hits, three linear discriminant equations combined with molecular docking simulations on specific proteins involved in ALS are reported, along with virtual screening of the Drugbank database as a practical example. In this particular case, as reported, a clinical trial has been already started for one of the drugs proposed in the present study.

Leveraging global multi-ancestry meta-analysis in the study of Idiopathic Pulmonary Fibrosis genetics

The research of rare and devastating orphan diseases such as Idiopathic Pulmonary Fibrosis (IPF) has been limited by the rarity of the disease itself. The prognosis is poor – the prevalence of IPF is only ∼4-times the incidence of the condition, limiting the recruitment of patients to trials and studies of the underlying biology of the disease. However, global biobanking efforts can dramatically alter the future of IPF research.Here we describe the largest meta-analysis of IPF, with 8,492 patients and 1,355,819 population controls from 13 biobanks around the globe. Finally, we combine the meta-analysis with the largest available meta-analysis of IPF so far, reaching 11,160 patients and 1,364,410 population controls in analysis.We identify seven novel genome-wide significant loci, only one of which would have been identified if the analysis had been limited to European ancestry individuals. We observe notable pleiotropy across IPF susceptibility and severe COVID-19 infection, beyond what is known to date. We also note a significant unexplained sex-heterogeneity effect at the strongest IPF locus MUC5B.

Updating preventive measures of children disability

The article provides an overview of special literature, which gives an opportunity to redefine some issues of disability prevention in children with rare (orphan) diseases, which will improve the organizational measures in this area. The prevention of children’s disability is considered as a system of measures to protect the health of the mother and child throughout childhood. The early disability prevention system in children and support for families raising children with disabilities remain among the main priorities of the State social policy of the Russian Federation. The authors describe modern technologies for reducing the genetic burden in the population from the point of view of preventing hereditary and congenital pathologies. They identify the priority areas of disability prevention in children with rare (orphan) diseases, i.e. introduction of prenatal and preimplantation diagnostics; use of the Prenatal Consultation organizational model; conducting a wider screening for congenital and hereditary metabolic diseases with the inclusion of the most common nosological forms of rare (orphan) diseases; finding pathogenetic therapy methods; increasing the knowledge of pediatricians about rare (orphan) diseases.

Study of the availability of gene therapeutic drugs in the Russian Federation

The authors studied the availability of gene therapy drugs in the Russian Federation on the basis of information on the permission of the medical use of drugs of this group in the world. Literature data and information about medicines approved by the FDA, EMA and the Ministry of Health of Russia were used. In general, the FDA registered only 13 drugs (46%) of the total approved for medical use in the world, 2 of them have already been withdrawn from the market, and 2 additional clinical trials are underway. In Europe, the EMA has approved 16 drugs for medical use (57%), with 4 of them already withdrawn. Most of the drugs were first approved by the FDA, and then, on average, a year later, were approved in the European market. A total of 4 drugs were approved in the European market and were not approved by the FDA at the time the data was requested. And only 1 drug, approved in the USA, is not registered in Europe. In the Russian Federation, two medicines are allowed, Neovasculgen (2011) and Spinraza (2019). This is only 7% of the total number of gene therapy drugs on the world market. Most of the drugs are intended for the treatment of orphan diseases and are cost expensive. This can explain the unevenness of their distribution across regions.

Health Technologies Assessment for Orphan Diseases. Example of Social and Economic Burden of Spinal Muscular Atrophy

Background. Studies of the economic impact of disease on society or the social and economic burden, known as developmental disease cost analysis, are equivalent to public health epidemiological studies. Spinal muscular atrophy (SMA) has significant social and economic burden according to various studies.Objective. The aim of the study is to compare Russian and international methodological approaches and results of health technology assessment (HTA) of SMA from the perspective of social and economic burden. Materials and methods. Literature searches were conducted using the Medline, PubMed, ClinicalTrials.gov, and Cochrane Library databases. Keywords and criteria for inclusion and exclusion have been used. The following parameters were used: costs, year of calculation, assessment method, primary and secondary results, type of economic assessment, perspective, time horizon, intervention, analysis of the sensitivity of the results. Both direct medical and non-medical costs were taken into account, as well as indirect costs.Results. The analysis of SMA burden the USA, Germany, Spain, Australia, France, Great Britain, and the Russian Federation was carried out based on 8 international studies and one Russian study that described the costs of SMA. All costs, including indirect ones, were estimated only in 4 international studies and in Russian one. The main source of information was either patient registers or cross-sectional retrospective studies of patients diagnosed with SMA. The costs were higher for type I SMA in all countries. The highest total SMA costs were in the United States, and the lowest in Russian Federation and Spain. Costs excluded new disease-modifying drugs such as nusinersen, risdiplam, and onasemogen abeparvovec in all conducted studies.Conclusions. The social and economic burden of SMA in Russian Federation in 2020 before the introduction of pathogenetic therapy into practice was 2.38 billion RUR/year. The costs of inpatient treatment and rehabilitation were 30.8 and 32.3% of total costs, respectively. These costs, before the introduction of pathogenetic therapy into practice, are lower than in Western Europe and United States, which is most likely since domestic studies used the standards of primary health care for children with SMA implemented in 2012, as well as low indirect costs for SMA in Russian Federation. Unified methodology for assessing the socio-economic significance of orphan diseases is required to carry out HTA of orphan diseases in Russian Federation. It should be based on domestic registries, otherwise on valid data, including those based on data from real clinical practice (RWD /RWE).

A Systematic Review and Meta-Analysis of the Prevalence of Congenital Myopathy

Background: Congenital myopathy constitutes a heterogeneous group of orphan diseases that are mainly classified on the basis of muscle biopsy findings. This study aims to estimate the prevalence of congenital myopathy through a systematic review and meta-analysis of the literature.Methods: The PubMed, MEDLINE, Web of Science, and Cochrane Library databases were searched for original research articles published in English prior to July 30, 2021. The quality of the included studies was assessed by a checklist adapted from STrengthening the Reporting of OBservational studies in Epidemiology (STROBE). To derive the pooled epidemiological prevalence estimates, a meta-analysis was performed using the random effects model. Heterogeneity was assessed using the Cochrane Q statistic as well as the I2 statistic.Results: A total of 11 studies were included in the systematic review and meta-analysis. Of the 11 studies included, 10 (90.9%) were considered medium-quality, one (9.1%) was considered low-quality, and no study was assessed as having a high overall quality. The pooled prevalence of congenital myopathy in the all-age population was 1.50 (95% CI, 0.93–2.06) per 100,000, while the prevalence in the child population was 2.73 (95% CI, 1.34–4.12) per 100,000. In the pediatric population, the prevalence among males was 2.92 (95% CI, −1.70 to 7.55) per 100,000, while the prevalence among females was 2.47 (95% CI, −1.67 to 6.61) per 100,000. The prevalence estimates of the all-age population per 100,000 were 0.20 (95% CI 0.10–0.35) for nemaline myopathy, 0.37 (95% CI 0.21–0.53) for core myopathy, 0.08 (95% CI −0.01 to 0.18) for centronuclear myopathy, 0.23 (95% CI 0.04–0.42) for congenital fiber-type disproportion myopathy, and 0.34 (95% CI, 0.24–0.44) for unspecified congenital myopathies. In addition, the prevalence estimates of the pediatric population per 100,000 were 0.22 (95% CI 0.03–0.40) for nemaline myopathy, 0.46 (95% CI 0.03–0.90) for core myopathy, 0.44 (95% CI 0.03–0.84) for centronuclear myopathy, 0.25 (95% CI −0.05 to 0.54) for congenital fiber-type disproportion myopathy, and 2.63 (95% CI 1.64–3.62) for unspecified congenital myopathies.Conclusions: Accurate estimates of the prevalence of congenital myopathy are fundamental to supporting public health decision-making. The high heterogeneity and the lack of high-quality studies highlight the need to conduct higher-quality studies on orphan diseases.

Inherited Proteoglycan Biosynthesis Defects—Current Laboratory Tools and Bikunin as a Promising Blood Biomarker

Proteoglycans consist of proteins linked to sulfated glycosaminoglycan chains. They constitute a family of macromolecules mainly involved in the architecture of organs and tissues as major components of extracellular matrices. Some proteoglycans also act as signaling molecules involved in inflammatory response as well as cell proliferation, adhesion, and differentiation. Inborn errors of proteoglycan metabolism are a group of orphan diseases with severe and irreversible skeletal abnormalities associated with multiorgan impairments. Identifying the gene variants that cause these pathologies proves to be difficult because of unspecific clinical symptoms, hardly accessible functional laboratory tests, and a lack of convenient blood biomarkers. In this review, we summarize the molecular pathways of proteoglycan biosynthesis, the associated inherited syndromes, and the related biochemical screening techniques, and we focus especially on a circulating proteoglycan called bikunin and on its potential as a new biomarker of these diseases.

The blood serum Na+/K+ ratio in orphan diseases

Введение. Концентрация Na+ и K+ в клетке и внеклеточной жидкости обусловливает фундаментальные свойства организма. В работе использовано Na+/К+ отношение сыворотки крови как патофизиологический критерий состояния человека при сходной патологии легких, но генетически разных орфанных заболеваниях. Цель исследования - изучение соотношения концентрации ионов Na+ и K+ в сыворотке крови как интегрального патофизиологического параметра базовой функции клеток при орфанных заболеваниях сопряженных с патологией легких. Методика. Обследованы 99 детей, в том числе 50 с 3 формами орфанной патологии легких. Среди них 24 ребенка с муковисцидозом (МВ), 15 детей с первичным иммунодефицитом (ПИД), 11 - с первичной цилиарной дискинезией (ПЦД). Контрольную группу- составили15 здоровых детей, группу сравнения - 34 пациента с внебольничной пневмонией, в том числе 15 с тяжелым течением. Возраст обследованных от 3 мес до 17 лет. Концентрация ионов Na+, K+, Cl-, измерялась ионоселективными электродами на анализаторе Erba XL-200, креатинина - кинетическим методом по реакции Яффе без депротеинизации на анализаторе Erba XL-200. Результаты. Концентрация Na+ и К+ в сыворотке крови у пациентов всех групп соответствовала стандартам нормы, однако расчет Na+/К+ отношения выявил статистически значимые отличия от показателей контрольной группы (30.40 ± 0.48) у пациентов с МВ, ПИД, ПЦД и при внебольничной пневмонии средней степени тяжести - 32.7±0.8, 33.2±0.9, 32.83±0.8 и 33±1, соответственно, (р<0.05). Различий при разных вариантах орфанных болезней не выявлено. Резкое увеличение Na+/K+ отношения наблюдалось в остром периоде пневмонии с тяжелым течением 38.8±1.1 (р<0.001). Повышение Na+/K+ отношения обусловлено снижением концентрации K+ в сыворотке крови. Клиренс креатинина сохраняется в границах нормы, что свидетельствует о сохранности гомеостатической, ионорегулирующей функции почек. Заключение. Na+/K+ отношение в сыворотке крови повышено у пациентов с орфанными заболеваниями органов дыхания и при пневмонии у детей. Острое увеличение Na+/K+ отношения в сыворотке наступает при резком ухудшении состояния пациентов. Высказано предположение, что увеличение Na+/K+ отношения в сыворотке крови обусловлено изменением функционального состояния клеток, их объема. Introduction. Concentrations of Na+ and K+ in the cell and in the extracellular fluid determine fundamental properties of the organism. The study used the blood serum Na+/K+ ratio as a pathophysiological criterion for the state of patients with similar pathologies of the lungs but with genetically different orphan diseases. The aim of the study was to evaluate the Na+/K+ concentration ratio in the blood serum as an integral pathophysiological parameter of the basic cell function in orphan diseases associated with lung pathology. Methods. 99 children were examined, including 24 with cystic fibrosis (CF), 15 with primary immunodeficiency (PIDs), and 11 with primary ciliary dyskinesia (PCD). The control group consisted of 15 healthy children and the comparison group consisted of 34 patients with community-acquired pneumonia, including 15 with severe disease. The patients aged from 3 mos. to 17 years. Concentrations of Na+, K+, and Cl- were measured with ion-selective electrodes on an Erba XL-200 analyzer; creatinine was measured by the kinetic method using the Jaffe reaction without deproteinization on an Erba XL-200 analyzer. Results. Concentrations of Na+ and K+ in blood serum in all groups corresponded to normal, standard values. The Na+/K+ ratio was 30.4±0.48 in healthy people, 32.7±0.8, 33.2±0.9, 32.83±0.8, and 33±1 in patients with CF, PIDs, PCD, or community-acquired pneumonia of moderate severity, respectively (р<0.05). All these values were significantly higher than in the control group (p < 0.05). However, there were no differences for different orphan diseases. A sharp increase in the Na+/K+ ratio was revealed in the acute period of severe pneumonia (38.8±1.1, p < 0.001). The increase in Na+/K+ ratio was due to a decrease in serum K+ concentration. The creatinine clearance remained within the normal range, which indicated preservation of the homeostatic, ion-regulating function of the kidneys. Conclusion. The Na+/K+ ratio is increased in patients with orphan respiratory diseases and in children with pneumonia. A sharp increase in the Na+/K+ ratio is a manifestation of acute deterioration of the patient’s condition. Apparently, the increase in serum Na+/K+ ratio is caused by a change in cell volume.

Socioeconomic characteristics and costs of rare and orphan diseases in Peru, 2019

Introduction: The rare and orphan diseases (ROD) constitute a current challenge due to the lack of investigation. Objective: Describe the socioeconomic characteristics of rare and orphan diseases (ROD) in Peru, 2019. Methods: Descriptive observational design. The information was obtained from FISSAL administrative records, and an intentional sample of 20 patients was taken to carry out the questionnaire on ROD. For the economic records, a review of the public budget of the MEF was made. The data analysis was descriptive and inferential. Results: There were 454 patients with a total of 49 ROD; of these, the most representative age groups were schoolchildren and young adults (18% each), and the most frequent diagnosis was Tetralogy of Fallot (22%). The questionnaire on ROD reports a median of 7 months in the delay of diagnosis and between 3 and 5 doctors were visited. Likewise, 30% considered that it generated a high to very high expense. It was calculated that the ROD budget constitutes 2.25% of the total budget for high-cost diseases. Likewise, the ROD budget was different between 2014 and 2019. Conclusions: The population with ROD in Peru is not large; however, it requires greater attention to access to health services and a greater budget allocation.